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Fasting gastric pH versus normal gastric pH

Fasting gastric pH versus normal gastric pH


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I want to know if someone is fasting (no food or drink for a whole day) will they have a higher or lower pH than a person who is eating regularly? If so what is an estimate of both of those pH's in the stomach?


The stomach linings generally secrete gastric acid (HCl, KCl and NaCl) and the native pH of the stomach is around 2. The longer you fast, gastric acid levels keep increasing until it reaches around 1-1.5. The food that you eat increases the pH levels of your stomach because the acid reacts with the food while digestion. Depending upon the type of food you eat, the pH levels of your stomach vary, but it is generally around 4-5 (again it varies depending upon the type and amount of food there is in the stomach).


Gastrin is one of the most important and clinically relevant hormones of the digestive system and has been studied extensively for the past decade. It is released by the G cells of the antrum of the stomach. Besides assisting in the stimulation of gastric acid secretion, it also facilitates proliferation of the gastric epithelial cells, tissue remodeling, and angiogenesis [1]. Abnormal gastrin production occurs in some clinical and diseased states, a condition known as hypergastrinemia and defined by a Gastrin level greater than 100� pg/ml [2].

It is necessary to monitor gastrin levels in a few conditions, including (i) refractory or recurrent peptic ulcer disease (PUD) in the absence of non-steroidal anti-inflammatory drugs or helicobacter pylori (H. pylori) infection, (ii) PUD in unusual locations (e.g. beyond the duodenal bulb), (iii) PUD with concurrent endocrinopathies, (iv) gastroesophageal reflux disease (GERD) refractory to proton pump inhibitors (PPIs) and/or with distal esophageal strictures, (v) presence of prominent rugal folds seen on upper endoscopy, (vi) chronic secretory diarrhea and (vii) gastric carcinoids. In these clinical conditions with abnormal gastrin production, it is therefore important to check for abnormal gastrin levels and to look for the source, if elevated. It is equally important for physicians and other practitioners to be aware of the clinical conditions in which gastrin monitoring is required and the implications of the results for the individual patient.

There has recently been immense interest in the pathophysiology of gastrin, due to extensive use of proton pump inhibitors (PPIs) and the resulting hypergastrinemia. PPI'S are available over the counter and are used indiscriminately for treating dyspepsia, acid reflux, gastritis and peptic ulcers without appropriate indication. H. pylori infection can, in general, also raise gastrin levels and it has become one of the most common reasons for hypergastrinemia. Some studies have raised concerns about the associated progression of colorectal cancer and occurrence of neoplasms of the stomach. The validity of these concerns is still under close scrutiny and is being studied extensively. Enterochromaffin-like (ECL) cell hyperplasia, and increased H. pylori-induced gastric atrophy has been noted in some recent studies, but their link to more severe diseases is yet to be determined. We present a review of the pathophysiology of gastrin secretion, as well as some known causes and implications of hypergastrinemia.


Contents

The gastrointestinal tract generates motility using smooth muscle subunits linked by gap junctions. These subunits fire spontaneously in either a tonic or a phasic fashion. Tonic contractions are those contractions that are maintained from several minutes up to hours at a time. These occur in the sphincters of the tract, as well as in the anterior stomach. The other type of contractions, called phasic contractions, consist of brief periods of both relaxation and contraction, occurring in the posterior stomach and the small intestine, and are carried out by the muscularis externa.

Motility may be overactive (hypermotility), leading to diarrhea or vomiting, or underactive (hypomotility), leading to constipation or vomiting either may cause abdominal pain. [3]

Stimulation Edit

The stimulation for these contractions likely originates in modified smooth muscle cells called interstitial cells of Cajal. These cells cause spontaneous cycles of slow wave potentials that can cause action potentials in smooth muscle cells. They are associated with the contractile smooth muscle via gap junctions. These slow wave potentials must reach a threshold level for the action potential to occur, whereupon Ca 2+ channels on the smooth muscle open and an action potential occurs. As the contraction is graded based upon how much Ca 2+ enters the cell, the longer the duration of slow wave, the more action potentials occur. This, in turn, results in greater contraction force from the smooth muscle. Both amplitude and duration of the slow waves can be modified based upon the presence of neurotransmitters, hormones or other paracrine signaling. The number of slow wave potentials per minute varies based upon the location in the digestive tract. This number ranges from 3 waves/min in the stomach to 12 waves/min in the intestines. [4]

Contraction patterns Edit

The patterns of GI contraction as a whole can be divided into two distinct patterns, peristalsis and segmentation. Occurring between meals, the migrating motor complex is a series of peristaltic wave cycles in distinct phases starting with relaxation, followed by an increasing level of activity to a peak level of peristaltic activity lasting for 5–15 minutes. [5] This cycle repeats every 1.5–2 hours but is interrupted by food ingestion. The role of this process is likely to clean excess bacteria and food from the digestive system. [6]

Peristalsis Edit

Peristalsis is one of the patterns that occur during and shortly after a meal. The contractions occur in wave patterns traveling down short lengths of the GI tract from one section to the next. The contractions occur directly behind the bolus of food that is in the system, forcing it toward the anus into the next relaxed section of smooth muscle. This relaxed section then contracts, generating smooth forward movement of the bolus at between 2–25 cm per second. This contraction pattern depends upon hormones, paracrine signals, and the autonomic nervous system for proper regulation. [4]

Segmentation Edit

Segmentation also occurs during and shortly after a meal within short lengths in segmented or random patterns along the intestine. This process is carried out by the longitudinal muscles relaxing while circular muscles contract at alternating sections thereby mixing the food. This mixing allows food and digestive enzymes to maintain a uniform composition, as well as to ensure contact with the epithelium for proper absorption. [4]

Every day, seven liters of fluid are secreted by the digestive system. This fluid is composed of four primary components: ions, digestive enzymes, mucus, and bile. About half of these fluids are secreted by the salivary glands, pancreas, and liver, which compose the accessory organs and glands of the digestive system. The rest of the fluid is secreted by the GI epithelial cells.

Ions Edit

The largest component of secreted fluids is ions and water, which are first secreted and then reabsorbed along the tract. The ions secreted primarily consist of H + , K + , Cl − , HCO3 − and Na + . Water follows the movement of these ions. The GI tract accomplishes this ion pumping using a system of proteins that are capable of active transport, facilitated diffusion and open channel ion movement. The arrangement of these proteins on the apical and basolateral sides of the epithelium determines the net movement of ions and water in the tract.

H + and Cl − are secreted by the parietal cells into the lumen of the stomach creating acidic conditions with a low pH of 1. H + is pumped into the stomach by exchanging it with K + . This process also requires ATP as a source of energy however, Cl − then follows the positive charge in the H + through an open apical channel protein.

HCO3 − secretion occurs to neutralize the acid secretions that make their way into the duodenum of the small intestine. Most of the HCO3 − comes from pancreatic acinar cells in the form of NaHCO3 in an aqueous solution. [5] This is the result of the high concentration of both HCO3 − and Na + present in the duct creating an osmotic gradient to which the water follows. [4]

Digestive enzymes Edit

The second vital secretion of the GI tract is that of digestive enzymes that are secreted in the mouth, stomach and intestines. Some of these enzymes are secreted by accessory digestive organs, while others are secreted by the epithelial cells of the stomach and intestine. While some of these enzymes remain embedded in the wall of the GI tract, others are secreted in an inactive proenzyme form. [4] When these proenzymes reach the lumen of the tract, a factor specific to a particular proenzyme will activate it. A prime example of this is pepsin, which is secreted in the stomach by chief cells. Pepsin in its secreted form is inactive (pepsinogen). However, once it reaches the gastric lumen it becomes activated into pepsin by the high H+ concentration, becoming an enzyme vital to digestion. The release of the enzymes is regulated by neural, hormonal, or paracrine signals. However, in general, parasympathetic stimulation increases secretion of all digestive enzymes.

Mucus Edit

Mucus is released in the stomach and intestine, and serves to lubricate and protect the inner mucosa of the tract. It is composed of a specific family of glycoproteins termed mucins and is generally very viscous. Mucus is made by two types of specialized cells termed mucus cells in the stomach and goblet cells in the intestines. Signals for increased mucus release include parasympathetic innervations, immune system response and enteric nervous system messengers. [4]

Bile Edit

Bile is secreted into the duodenum of the small intestine via the common bile duct. It is produced in liver cells and stored in the gall bladder until release during a meal. Bile is formed of three elements: bile salts, bilirubin and cholesterol. Bilirubin is a waste product of the breakdown of hemoglobin. The cholesterol present is secreted with the feces. The bile salt component is an active non-enzymatic substance that facilitates fat absorption by helping it to form an emulsion with water due to its amphoteric nature. These salts are formed in the hepatocytes from bile acids combined with an amino acid. Other compounds such as the waste products of drug degradation are also present in the bile. [5]

The digestive system has a complex system of motility and secretion regulation which is vital for proper function. This task is accomplished via a system of long reflexes from the central nervous system (CNS), short reflexes from the enteric nervous system (ENS) and reflexes from GI peptides working in harmony with each other. [4]

Long reflexes Edit

Long reflexes to the digestive system involve a sensory neuron sending information to the brain, which integrates the signal and then sends messages to the digestive system. While in some situations, the sensory information comes from the GI tract itself in others, information is received from sources other than the GI tract. When the latter situation occurs, these reflexes are called feedforward reflexes. This type of reflex includes reactions to food or danger triggering effects in the GI tract. Emotional responses can also trigger GI response such as the butterflies in the stomach feeling when nervous. The feedforward and emotional reflexes of the GI tract are considered cephalic reflexes. [4]

Short reflexes Edit

Control of the digestive system is also maintained by ENS, which can be thought of as a digestive brain that can help to regulate motility, secretion and growth. Sensory information from the digestive system can be received, integrated and acted upon by the enteric system alone. When this occurs, the reflex is called a short reflex. [4] Although this may be the case in several situations, the ENS can also work in conjunction with the CNS vagal afferents from the viscera are received by the medulla, efferents are affected by the vagus nerve. When this occurs, the reflex is called vagovagal reflex. The myenteric plexus and submucosal plexus are both located in the gut wall and receive sensory signals from the lumen of the gut or the CNS. [5]

Gastrointestinal peptides Edit

For further information see Gastrointestinal hormone

GI peptides are signal molecules that are released into the blood by the GI cells themselves. They act on a variety of tissues including the brain, digestive accessory organs, and the GI tract. The effects range from excitatory or inhibitory effects on motility and secretion to feelings of satiety or hunger when acting on the brain. These hormones fall into three major categories, the gastrin and secretin families, with the third composed of all the other hormones unlike those in the other two families. Further information on the GI peptides is summarized in the table below. [7]


Fasting gastric pH versus normal gastric pH - Biology

The stomach has a pH between 1.5 and 3.5 generally and this is due to the cells in the stomach releasing hydrochloric acid. The low pH is useful for “unraveling” proteins making them easier to digest and killing bacteria and other pathogens. The intestine on the other hand is around pH 6 to 7 which is important because the low pH of the stomach is potentially dangerous to the body. Therefore, it makes sense to only have the stomach being really acidic rather than the whole digestive tract. To facilitate the change from low pH in the stomach to mid pH in the intestine, there are cells that release sodium bicarbonate. Sodium bicarbonate is more commonly known as baking soda and is useful for neutralizing acids. So as cells in the intestines gradually release more and more sodium bicarbonate, the pH raises from around 1 to around 7.

The stomach usually has a pH of 2 or 3. That’s still really acidic. The stomach is protected by having a layer of mucus between the inside the stomach and the actual stomach tissue. Some of the cells that line the stomach also make a buffer (a high-pH liquid) that helps to keep the pH right by the cells closer to neutral.

When there is nothing in the stomach, less acid is produced. This may seem like a waste of energy and materials, creating a low pH, then trying to protect itself. The acidic environment of the stomach is important, though. Not only does it help to break down certain foods, it kills germs before they enter the small intestine. The lining of the small intestine is more delicate so that nutrients can be absorbed there.

The small intestine stays close to neutral because the pancreas dumps a lot of buffers in right where the stomach connects to the small intestine. This pH is much closer to water and does not damage the tissue.

Why do you think the digestive system has zones that are so different from each other?


Fasting gastric pH versus normal gastric pH - Biology

As with most questions that pertain to human anatomy there is a lot of natural variation. The normal human stomach has a pH which can range from approximately 1-3 but is usually closer to 2. When there is food in the stomach the pH can raise to as high as 4-5. After the food leaves the stomach bicarbonate ions are secreted to neutralize and alkalinize the mixture. The pH of the small intestine is approximately 8.

As far as how long food stays in your stomach it depends on what that food is.
Some foods that contain simple carbohydrates (such as sugar or white bread) are relatively fast to digest compared to more complex carbohydrates or proteins.
Foods contain a variety of different levels of carbohydrates, fats, oils, protein, fiber, etc. all of which have different mechanisms and rates of digestion. If for example you eat some trail mix, the chocolate chips will be digested rapidly, the fruit will take longer, and the nuts could take several hours. The range in digestion times is large: if the stomach is empty water will leave immediately and go to the intestines, whereas meats such as beef and pork can take upwards of 4 hours.
Its a short answer but hope it helps.

The pH of your stomach acid is pH 1 to 3, which is a strong acid. (This is when it's empty and pH 5 when it's full.)

Meat spends 3-6 hours in the stomach, or longer if there is fat in the stomach, too. Water and alcohol are absorbed on a time scale of seconds to minutes through the mouth, stomach and digestive tract.

I learned in a nutrition class that the old picture of the stomach is a bag with all our food mixed up in it. The new view of our stomach is a bag with all our swallows of food lying one on top of each other, and the stomach digests the food and passes it to the intestine, starting at the outside layer of food. Scientists discovered that by doing some sort of experiments where people ate food that could be seen with x-rays or some sort of imaging system.

Stomach acid pH ranges between about 1 and 2. Although it can vary depending on what you choose to consume, food typically spends about 4 hours in the stomach before it reaches the appropriate consistency and enters the intestine


pH stands for Potential Hydrogen, degree of concentration of H ions in the substance or a solution.

  • pH value of 0 (strongly acidic) to less than 7 (mild acidic) is acid, molecules that give off H (hydrogen) maintain an acidic pH
  • pH of 7 means neutral
  • pH of greater than 7 (mild alkali) to 14 (strong alkali) means base, molecules that attract H (hydrogen) maintain a basic (alkaline) pH
  • pH controls the speed of our body's biochemical reactions.
  • Acid pH is hot & fast and alkaline pH is cool & slow.

Let food be your medicine.
Let medicine be your food. - Hippocrates

What we eat and drink will affect where our body's pH level falls, and our body's pH will control the activity of every metabolic function happening in our body.

pH is behind the body's electrical system and intracellular activity as well as the way our bodies utilize enzymes, minerals, and vitamins.
The pH varies in the digestive process from stage to stage:

  • In the mouth, the pH is in neutral (or close to neutral),
  • In the stomach, the pH is acidic at around two.
  • In the small intestine, the pH is basic at around 8
  • Finally, it reaches seven as it reaches the end (anus).

Esophagus pH - Near pH neutral Digestion process

The first digestion process starts at the mouth it has a pH of 6.8 to 7.2 that is near neutral or mildly acidic/basic. This pH is causing by the salivary glands in the mouth this pH range helps your food to start digestion from the mouth until it reaches the stomach through the esophagus by salivary enzyme amylase. It helps to break down carbohydrates into monosaccharide.

Stomach pH - Acidic pH Digestion process

At the time of food reaches the stomach, Stomach is at high acidic pH of 1.3, due to the secretion of hydrochloric acid. This helps to kill harmful microorganisms, denature protein for digestion, and help create a favorable atmosphere to the enzymes in the stomach. The stomach smashes the food into chyme and prepares it for the small intestine to further breakdown of food and absorption of nutrients.

Small Intestine pH - Alkaline (base) pH Digestion process

The chyme from the stomach moves down into the small intestine, secretes sodium bi carbonate to make it slightly alkali to the pH of 7 to 8. Further breakdown of protein and fat takes place, and absorption of nutrients takes place.


Discussion

Gastric ulcer is one of the most important problems in developing countries that may be attributed to the exposure of stomach mucosa to various harmful factors (Antwi et al., 2009). The detailed etiopathogenesis of this ailment is still unclear (Ramamurthy and Marueen, 2018). The current study searched the effects of PLN against IND-induced gastric ulcers, and compared the effects with traditional PPE. Increased consumption of NSAIDs was believed to be responsible for nearly 25% of gastric ulcer cases (Adhikary et al., 2011). Of them, Indomethacin, an effective medicine used in chronic arthritis, is most frequently cited as a cause of gastric mucosal injury. In addition to causing gastric ulceration, it also delays ulcer healing (Hawkins and Hanks, 2000). This was proved in our study by the appearance of multiple ulcers, a marked increase in the ulcer index, structural alterations in the sections from fundic gastric mucosa that appeared in the form of patchy areas of erosions and ulcerations together with loss of gastric pits, and a noticeable prominent leucocyte infiltration in the lamina propria, confirming the inflammatory triggering role of IND.

Excessive generation of free radicals, inflammatory cytokines, and increased HCL secretion were assumed to be the underlying mechanisms of IND-mediated gastric mucosal injury. The present study revealed a marked increase in the serum levels of MDA, a common metabolite of lipid peroxidation, and decreased TAC generating a condition of oxidative overload. This was partially in concordance with previous studies (Liu et al., 2015 Al-Quraishy et al., 2017 Gomaa et al., 2018). This may be attributed to IND-mediated suppression of the respiratory chain with the resulting release of mitochondrial cytochrome c into the cytosol and subsequent generation of reactive oxygen species. Thereafter, progressive intracellular ATP depletion, liberation of lysosomal enzymes, hydroxyl anion mediated degeneration of hyaluronic acid, the basic constituent of epithelial cells basement membrane, as well as peroxidation of tissue lipids, proteins, and nucleic acids represent prominent consequences of raised free radical formation culminating in mucosal injury (Matsui et al., 2011). Furthermore, the free radicals enhanced vascular permeability with an enrollment of motivated neutrophils into the gastric mucosa (El-Abhar, 2010) that adhere directly to gastric endothelium, occluding microvasculature and decreasing mucosal blood flow, leading to ulceration (Shim and Kim, 2016).

The probable danger of extensive oxidative stress is its ability to provoke an inflammatory response in gastric mucosa (Sun et al., 2015). The role of inflammatory cytokines in the pathogenesis of gastric ulcers was documented in former studies (El-Ashmawy et al., 2016 Katary and Salahuddin, 2017 Gomaa et al., 2018 Abdelfattah et al., 2019). The marked increase in levels of inflammatory mediators IL2, IL6 in the serum of IND-treated rats, in addition to an intense increase in the count of TNF-alpha gastric mucosal immunopositive cells and diminished serum anti-inflammatory cytokine IL10 levels, found in the present study, proved this hypothesis. A major contributor to IND-induced gastric mucosal injury was shown to be TNF-α (Souza et al., 2004). This pro-inflammatory cytokine, together with oxidants, activate the nuclear factor kappa B (NF-㮫) pathway through phosphorylating and suppressing its inhibitor IKB, with subsequent translocation into the nucleus to start transcription of other inflammatory genes that, in turn, induce formation of adhesion molecules on the cell membrane of both neutrophil and endothelial cells facilitating their attraction (Lawrence, 2009 Abdelfattah et al., 2019), thereby accounting for the massive neutrophil and other inflammatory cell infiltration observed in our results. A previous study conducted by Paul (2013) postulated the increased TNF-α expression to be an indicator of gastric inflammation. It is worth noting that infiltrating inflammatory cells could be a major source of reactive oxygen species and subsequent oxidative status (Ganguly and Swarnakar, 2012). Hence, a vicious cycle of inflammation and excessive free radical generation was created in the gastric mucosa overthrowing natural antioxidant defense mechanisms and explaining mucosal injury. These findings were verified by negative correlations between TAC and IL2 in the IND-treated group.

Maintenance of a healthy gastric epithelial mucosal barrier is postulated to depend on adequate gastric PGE2 and NO levels. Prostaglandin E2 was assumed to increase mucous and bicarbonate ion release, mucosal blood flow, and reduced gastric HCL secretion (Rahim et al., 2014). Nitric oxide in the gastric mucosa works in a paradoxical manner. It is synthesized from L-Arginine in a chemical reaction catalyzed by either cytoprotective constitutive eNOS or by cytotoxic inducible nitric oxide synthase (iNOS) (Abdel-Raheem, 2010). NO generated from eNOS promotes ulcer healing through stimulating vasodilatation, inducing the formation of new blood vessels, quenching free radicals, and ameliorating aggregation of leucocytes resulting in the restitution of epithelial tissue integrity with the increased mucous release (Nishida et al., 1998 Khattab et al., 2001). Furthermore, NO generated from iNOS, function in gastric ulcer induction via the formation of reactive oxygen species and toxic effects on cells (Cho, 2001).

Herein, levels of PGE2, NO were markedly attenuated in the gastric ulcer group in compliance with formerly published studies (El-Ashmawy et al., 2016 Allam and El-Gohary, 2017), confirming the ulcerogenic effect of IND via increasing HCL secretion. This decrement of gastric PGE2 level results in increased gastric acid secretion agreeing with previous reports (Adhikary et al., 2011 Ashraf et al., 2012) where IND was reported to cause alterations in gastric secretions of rats. The predominance of parietal cells in ulcerated regions detected in our histological sections confirm previous findings (Wallace, 2008) where IND significantly augmented acid secretion of parietal cells. At the same time, it did not show any effect on the basal secretion of bicarbonate ions from surface mucous cells. The state of oxidative stress in the gastric mucosa was incriminated in the reduction of PGE2 as a result of the inhibition of mucosal cell COX, a rate-limiting enzyme of prostaglandin synthesis, or, may be due to the transformation of PGE2 to 8 iso-PGF2 alpha, a metabolic end-product of oxidation (Allam and El-Gohary, 2017). The former investigators (Katary and Salahuddin, 2017) clarified the decreased gastric NO content to be due to IND-mediated suppression of gastric eNOS enzyme activity. The genetic and immunohistochemical results of the IND-treated group substantiated this hypothesis where ulcerated tissues showed a significant reduction of eNOS mRNA expression and a decrease in the mean count of eNOS immunopositive cells compared to the control.

Despite the lack of sure scientific evidence supporting the use of herbal extracts in medical fields, the branch of phytotherapy is still considered a supplementary or a complementary prescription for the prevention and treatment of several pathologies (Cravatto et al., 2010). The pomegranate is a highly nutritious fruit, containing many beneficial agents such as polyphenols, alkaloids, tannins and flavonoids, vitamin C, and minerals. These substances possess several therapeutic effects (Elfalleh et al., 2011). Oral intake of either PLN or traditional PPE demonstrated significant reductions of ulcer index, oxidant mediator MDA, inflammatory cytokines IL-2, IL-6, and TNF-α immune-expression in gastric mucosa accompanied with marked elevation of serum levels of TAC, IL-10 denoting alleviation of the stressful conditions of oxidation and inflammation. These results partially agree with previous findings (Chauhan et al., 2017, 2018 Katary and Salahuddin, 2017). The administration of PLN caused about 97.06% inhibition as compared to 76.48% inhibition with ordinary PPE. The gastroprotective effects of punicalagin (found in pomegranate juice) against an ethanol-induced gastric ulcer were confirmed (Katary and Salahuddin, 2017) to be achieved by reducing the protein expression of NF-kB, TNF-α gene expression. A previous study (Rafraf et al., 2017) attributed the anti-inflammatory effect of pomegranate to the downregulation of cytokines such as TNF-α, IL-1, and IL-6. The authors explained that this improvement was due to the polyphenolic contents of the pomegranate, which produce strong antioxidant, anti-inflammatory, and tissue repair properties. The negative correlations between ulcer index and IL2 in the PPE-treated group, and the positive correlation between TAC and IL10 in the PLN-treated group, verified our results.

The basic mechanism for reducing oxidative overload by PPE was via upregulation of the cytoplasmic transcription factor Nrf2, by disturbing the Nrf2-Keap1 complex, facilitating the entry of Nrf2 into the nucleus and binding to DNA, enhancing the transcription of the antioxidant genes with consequent increased generation of natural cellular antioxidant enzymes. This, in turn, restored the cellular redox balance, reinforcing the cellular resistance to various harmful agents (Al-Quraishy et al., 2017 Kandeil et al., 2018). A recent study (Patel et al., 2019) explained the antioxidant capacity of PPE to the presence of ellagic acid, where its oxidant scavenging activity was potentiated by anthocyanins phenolic constituents of the extract. Moreover, Hydroxyl and carboxyl groups present in organic compounds of the extract helped them to chelate metal ions and abolish their oxidant damaging effects.

Endothelial nitric oxide synthase exists intracellularly in normal gastric mucosa with distinct distribution patterns showing a greater expression in the corpus and antrum than in the proximal third of the normal human stomach (Rajnakova et al., 1997). The macrophages, endothelial cells, and neural elements in the stomach wall also showed eNOS immunoreactivity (Shapiro and Hotchkiss, 1996). The importance of NO in the modulation of gastric ulcer healing had recently been elucidated (Sistani Karampour et al., 2019). Administration of NO donors can hasten the healing of a gastric ulcer (El-Abhar, 2010). In this experimental study, the levels of gastric PGE2 and NO were markedly elevated in rats treated with pomegranate peels, both in the natural extract formula and in bound form to chitosan nanoparticles. These results were in compliance with the previous findings (Sistani Karampour et al., 2019).

In the present study, we confirmed this latter finding where the PPE treated group showed a marked upregulation of eNOS mRNA expression and prominent positive eNOS immunostained cells in the vascular endothelium, surface epithelium, and glandular epithelial cells of the stomach mucosa, thereby replenishing the reduced eNOS found in the IND-treated group. This wide expression in several areas ensures enough supply of NO. This result was ascertained by the positive relationship between NO and PGE2 in PLN-treated rats and negative correlations between NO, each ulcer index, and MDA in PPE-treated groups.

The ability of pomegranate to promote local gastric defense mechanisms as well as re-epithelialization and regeneration of glandular architecture of stomach mucosa observed in the histological sections is attributed to its active ingredients. The polyphenolic constituents of pomegranate stimulate the formation of tissue growth factors, prostaglandins, eNOS-mediated NO generation, boosting endogenous antioxidant mucosal status, chelating oxidative agents, and suppressing anti-angiogenic factors (Al-Rehaily et al., 2002). Furthermore, tannins, another beneficial component of PPE, promoted healing of the ulcer by stimulating the precipitation of microproteins at the ulcerative site, thus forming a protective layer against irritants over gastric mucosa and inhibiting gastric secretions at the injury site (Chang et al., 2005). It was postulated that the antioxidant capacity of prepared pomegranate rind extract in methanol is greater than the seeds. The polyphenolic contents of pomegranate are higher when compared with different fruits such as an apple, grapefruit, pineapple, grapes, and an orange (Chidambara Murthy et al., 2002 Raja et al., 2007).

Moreover, the alkaloids constituents of PPE increase the pH of gastric contents by reducing HCL secretion, while flavonoids are capable of chelating free radicals due to the lack of electrons in their chemical structure, thus ameliorating oxidative injury to gastric mucosa (Ramamurthy and Marueen, 2018). Another study conducted by Ansar et al. (2019) reported that the antioxidant activity of PPE might be similar to curcumin due to the presence of the hydroxyl (- OH) group, that prohibits oxidative breakage of the -SH group, thus, preserving the thiol content of tissues protecting against oxidation of cellular proteins.

In the field of nanotechnology, a fantastic breakthrough in the science of improving the healing properties of the ulcerhas been made (Lim et al., 2016). Nanoparticles are a drug delivery tool that can be used either as a drug carrier or as the treatment itself (Ghosh et al., 2012). In this study, the nanosized pomegranate particles ranged in size between 299 and 900 nm with a PDI from 0.2 to 0.5. The nanoparticle size decreased when increasing the CS/TPP ratio, which might be due to the increase in the amount of chitosan, thus increasing the electrostatic interactions between chitosan and pomegranate. The pomegranate-loaded nanoparticles had a spherical shape and encapsulation efficiency of about 85 ± 0.6%, with positive surface charges due to the presence of excess chitosan functional amine groups. These positive surface charges of PLN were crucial in determining the electrostatic interactions and adhesion characteristics with the gastric mucosa. It was reported by Salama et al. (2019) that the transport of nanoparticles that have positive charges through epithelial cellular membranes was greater than the molecules that have no or negative charges, hence, enhancing their bioavailability.

Additionally, the stability study of PLN confirmed that the nanoparticles had sufficient stability over a long incubation period. These results established the role of TPP as a stabilizer as well as its ability to form strong electrostatic interactions and to form stable structures that are less able to aggregate and coalesce (Raja et al., 2015). This explains the effectiveness of PLN in curing the gastric ulcer, proven by the full restoration of biochemical, genetic, histopathological, and immunohistochemical alterations when compared with PPE-treated rats.

In conclusion, PLN and PPE can potently correct the harmful effects of IND on the gastric mucosa. This effect is more pronounced with PLN the antiulcer activity of PPE can be ascribed to oxidant lowering and anti-inflammatory actions that in turn promote gastric protective factors (NO, PGE2), enhance stomach eNOS mRNA and protein expression, and markedly ameliorate all histopathological alterations. This study, therefore, offers new therapeutic agents for IND-induced gastric ulcers. However, future research is recommended to further explore the exact mechanism of pomegranate nanoparticles and to clarify their safety levels.


Acknowledgements

Declaration of personal interests: Richard Holloway has served as a speaker and consultant for AstraZeneca and Janssen-Cilag, and has received research funding from Nycomed. John Dent has received consulting fees for advisory committees/review panels, consulting, speaking and teaching, and grant/research support for basic science research, from AstraZeneca. Robert Fraser has served as consultant or speaker for GlaxoSmithKline, Nycomed and Johnson and Johnson, and has received research funding from GlaxoSmithKline. Declaration of funding interests: This study was funded in part by a Grant-in-Aid from AstraZeneca.

Table S1. Primer sequences and annealing temperatures for DNA methylation analysis.

Table S2. The median (interquartile range) amount of methylation (T50) in all squamous and columnar biopsies.

Table S3. The median (interquartile range) amount of methylation (T50) in columnar biopsies from patients on standard proton pump inhibitor (PPI) and following 40 mg twice-daily (high-dose) esomeprazole for 6 months.

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Do You Need pH Balancing?

The pH scale measures the potency of acids and bases, where higher scores are more basic and lower scores are more acidic. Correct pH levels are essential for delivering oxygen to your tissues. Your pH level affects several biochemical reactions and helps to ensure the proper structures of proteins the body produces. The pH balance in the female body even affects vaginal hygiene and may cause vaginal dryness.

So what are the safe ranges for pH levels? You need to stay between 7.35 and 7.45, according to a study from the April 2018 issue of Nutrients. That means that it's not something you should try to alter without talking with your doctor first. Your body has mechanisms in place to help keep the right balance. As long as you're healthy, your lungs and your kidneys will maintain your pH balance correctly without outside intervention.

This means that if your body pH goes under 7.35 and enters a state of acidemia, it will try to induce alkalosis. Alkalosis means that your body pH goes above 7.45. That's why you don't want to try balancing your pH levels without seeking medical advice from a physician first. You could end up increasing a problem when you aren't fully aware of the details. It's similar to taking vitamins to supplement a nutritional deficiency that you haven't actually confirmed.


Footnotes

Peer reviewers: Andrzej S Tarnawski, MD, PhD, DSc (Med), Professor of Medicine, Chief Gastroenterology, VA Long Beach Health Care System, University of California, Irvine, 5901 E. Seventh Str., Long Beach, CA 90822, United States Ferruccio Bonino, MD, PhD, Professor of Gastroenterology, Director of General Medicine 2 Unit, Director of Liver and Digestive Disease Division, Department of Internal Medicine, University Hospital of Pisa, University of Pisa, Via Roma 67, 56124 Pisa, Italy



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